Method for reducing oxalate

ABSTRACT

A method for reducing oxalate levels in a patient that includes administering to the patient a therapeutically effective amount of non-absorbable amine polymers such as a polymer characterized by a repeat unit having the formula:  
                 
 
     and salts and copolymers thereof, where n is a positive integer and x is zero or an integer between 1 and about 4.

RELATED APPLICATIONS

[0001] This application is a Continuation of U.S. application Ser. No.09/668,874, filed Sep. 25, 2000 which is a Continuation of U.S.application Ser. No. 09/359,226, filed Jul. 22, 1999 which is aContinuation of U.S. application Ser. No. 08/964,956, filed Nov. 5,1997, the entire teachings of which are incorporated herein byreference.

BACKGROUND OF THE INVENTION

[0002] Approximately 0.1% of adults in the USA are hospitalized eachyear for urinary calculi (e.g. kidney stones), of which about 80% areprimarily calcium oxalate. Patients at risk for urinary calculigenerally include those with calculi or who have had calculi in thepast, those with renal insufficiency, those on diets containing a largeamount of oxalate, those with ileal disease, ileal resection, orjejeunoileal bypass, those with chronic biliary or pancreatic disease,and those with a family history of calculi. Thus, there is a need forsuperior oxalate reducers.

SUMMARY OF THE INVENTION

[0003] The invention relates to the discovery that a class of polymershave improved oxalate binding properties. The polymers employed in theinvention comprise water-insoluble, non-absorbable, and optionallycross-linked polyamines as defined herein. The polyamines of theinvention can be amine or ammonium containing aliphatic polymers. Byaliphatic amine polymers, it is meant a polymer which is manufactured bypolymerizing an aliphatic amine monomer. In a preferred embodiment, thepolymers are characterized by one or more monomeric units of Formula I:

[0004] and salts thereof, where n is a positive integer and x is 0 or aninteger between 1 and about 4, preferably 1. In preferred embodiments,the polymer is crosslinked by means of a multifunctional crosslinkingagent.

[0005] The invention provides an effective treatment for removingoxalate from a patient (and thereby reducing the patient's urinaryoutput of oxalate and urinary calculi).

[0006] The invention also provides for the use of the polymers describedherein for the manufacture of a medicament for the treatment of urinarycalculi, for oxalate binding or reduction of oxalate levels.

[0007] Other features and advantages will be apparent from the followingdescription of the preferred embodiments thereof and from the claims.

DETAILED DESCRIPTION OF THE INVENTION

[0008] As described above, the polymers employed in the inventioncomprise water-insoluble, non-absorbable, optionally cross-linkedpolyamines. Preferred polymers are polyallylamine, polyvinylamine andpolydiallylamine polymers. The polymers can be homopolymers orcopolymers, as discussed below, and can be substituted or unsubstituted.These and other polymers which can be used in the claimed invention havebeen reported in the patent literature in, for example, U.S. Pat. Nos.5,487,888, 5,496,545, 5,607,669, 5,618,530, 5,624,963, 5,667,775,5,679,717, 5,703,188, 5,702,696 and 5,693,675. Copending U.S.application Ser. Nos. 08/659,264, 08/823,699, 08/835,857, 08/470,940,08/826,197, 08/777,408, 08/927,247, 08/964,498 and 08/964,536, theentire contents of which are incorporated herein by reference.

[0009] The polymer can be a homopolymer or a copolymer of one or moreamine-containing monomers or a copolymer of one or more amine-containingmonomers in combination with one or more non-amine containing monomers.Where copolymers are manufactured with the monomer of the above FormulaI, the comonomers are preferably inert, non-toxic and/or possess oxalatebinding properties. Examples of suitable non-amine-containing monomersinclude vinylalcohol, acrylic acid, acrylamide, and vinylformamide.Examples of amine containing monomers preferably include monomers havingthe Formula 1 above. Preferably, the monomers are aliphatic. Mostpreferably, the polymer is a homopolymer, such as a homopolyallylamine,homopolyvinylamine or homopolydiallylamine.

[0010] Other preferred polymers include polymers characterized by one ormore repeat units set forth below

[0011] or copolymers thereof, wherein n is a positive integer, y and zare both integers of one or more (e.g., between about one and about 10)and each R, R₁, R₂, R₃ and R₄, independently, is H or a substituted orunsubstituted alkyl group (e.g., having between 1 and 25 or between 1and 5 carbon atoms, inclusive), alkylamino (e.g., having between 1 and 5carbons atoms, inclusive, such as ethylamino or poly(ethylamino)) oraryl (e.g., phenyl) group, and each X⁻is an exchangeable negativelycharged counterion.

[0012] In one preferred polymer, at least one of R, R₁, R₂, R₃ or R₄groups is a hydrogen atom. In a more preferred embodiment, each of thesegroups are hydrogen.

[0013] In each case, the R groups can carry one or more substituents.Suitable substituents include therapeutic anionic groups, e.g.,quaternary ammonium groups, or amine groups, e.g., primary, secondary ortertiary alkyl or aryl amines. Examples of other suitable substituentsinclude hydroxy, alkoxy, carboxamide, sulfonamide, halogen, alkyl, aryl,hydrazine, guanadine, urea, poly(alkylenimine), such as(polyethylenimine) and carboxylic acid esters, for example. Preferably,the polymer is rendered water-insoluble by crosslinking. Thecross-linking agent can be characterized by functional groups whichreact with the amino group of the monomer. Alternatively, thecrosslinking group can be characterized by two ore more vinyl groupswhich undergo free radical polymerization with the amine monomer.

[0014] Examples of suitable crosslinking agents include diacrylates anddimethylacrylates (e.g. ethylene glycol diacrylate, propylene glycoldiacrylate, butylene glycol diacrylate, ethylene glycol dimethacrylate,propylene glycol dimethacrylate, butylene glycol dimethacrylate,polyethyleneglycol dimethacrylate and polyethyleneglycol diacrylate),methylene bisacrylamide, methylene bismethacrylamide, ethylenebisacrylamide, ethylene bismethacrylamide, ethylidene bisacrylamide,divinylbenzene, bisphenol A, dimethacrylate and bisphenol A diacrylate.The crosslinking agent can also include acryloyl chloride,epichlorohydrin, butanedioldiglycidyl ether, ethanedioldiglycidyl ether,succinyl dichloride, the diglycidal ether of bisphenol A, pyromelliticdianhydride, toluene diisocyanate, ethylene diamine and dimethylsuccinate.

[0015] A preferred crosslinking agent is epichlorohydrin because of itshigh availability and low cost. Epichlorohydrin is also advantageousbecause of its low molecular weight and hydrophilic nature, increasingthe water-swellability and gel properties of the polyamine.

[0016] The level of crosslinking makes the polymers insoluble andsubstantially resistant to absorption and degradation, thereby limitingthe activity of the polymer to the gastrointestinal tract. Thus, thecompositions are non-systemic in their activity and will lead to reducedside-effects in the patient. Typically, the cross-linking agent ispresent in an amount from about 0.5-35% or about 0.5-25% (such as fromabout 2.5-20% or about 1-10%) by weight, based upon total weight ofmonomer plus crosslinking agent. The polymers can also be furtherderivatized, such as alkylated amine polymers, as described, forexample, in U.S. Pat. Nos. 5,679,717, 5,607,669 and 5,618,530, which areincorporated herein by reference. Preferred alkylating agents includehydrophobic groups (such as aliphatic hydrophobic groups) and/orquaternary ammonium- or amine-substituted alkyl groups.

[0017] Non-cross-linked and cross-linked polyallylamine andpolyvinylamine are generally known in the art and are commerciallyavailable. Methods for the manufacture of polyallylamine andpolyvinylamine, and cross-linked derivatives thereof, are described inthe above U.S. Patents, the teachings of which are incorporated entirelyby reference. Harada et al. (U.S. Pat. Nos. 4,605,701 and 4,528,347,which are incorporated herein by reference in their entirety) alsodescribe methods of manufacturing polyallylamine and cross-linkedpolyallylamine. As described above the polymer can be administered inthe form of a salt. By “salt” it is meant that the nitrogen group in therepeat unit is protonated to create a positively charged nitrogen atomassociated with a negatively charged counterion.

[0018] The cationic counterions can be selected to minimize adverseeffects on the patient, as is more particularly described below.Examples of suitable counterions include organic ions, inorganic ions,or a combination thereof, such as halides (Cl⁻ and Br⁻ ) CH₃OSO₃ ⁻, HSO₄⁻, SO₄ ²⁻, HCO₃ ⁻, CO₃ ⁻, acetate, lactate, succinate, propionate,butyrate, ascorbate, citrate, dihydrogen citrate, tartrate,taurocholate, glycocholate, cholate, hydrogen citrate, maleate,benzoate, folate, an amino acid derivative, a nucleotide, a lipid, or aphospholipid. The counterions can be the same as, or different from,each other. For example, the polymer can contain two different types ofcounterions.

[0019] The polymers according to the invention can be administeredorally to a patient in a dosage of about 1 mg/kg/day to about 1g/kg/day, preferably between about 10 mg/kg/day to about 200 mg/kg/day;the particular dosage will depend on the individual patient (e.g., thepatient's weight and the extent of oxalate removal required). Thepolymer can be administrated either in hydrated or dehydrated form, andcan be flavored or added to a food or drink, if desired to enhancepatient acceptability. Additional ingredients such as other oxalatereducers or binders (including calcium), ingredients for treating otherrelated indications, or inert ingredients, such as artificial coloringagents can be added as well.

[0020] For example, an enzyme which can reduce oxalate levels can becoadministered with the polymer. Suitable enzymes include oxalatedecarboxylase, oxalate oxidase and additional enzymes that can functioncollaterally and, for example, convert products of the enzymaticreaction to harmless products. For example, peroxidase can beadministered to convert hydrogen peroxide produced by oxalate oxidase.

[0021] The additional active ingredients, such as enzymes, can beadministered simultaneously or sequentially with the oxalate bindingpolymer. Where the ingredients are administered simultaneously, theenzyme can optionally be bound to the polymer, for example, by covalentbonding or physically encapsulating the enzyme, on the exterior orinterior of the polymeric particle. Covalent bonding can be accomplishedby reacting the polymer and enzyme(s) with a suitable crosslinkingagent. For example, polyallylamine and an enzyme can be cross-linkedwith epichlorohydrin, polyacrylamide and an enzyme can be cross-linkedwith methylenebisacrylamide and poly-2-acrylamido-2-methylpropanesulfonic acid (and its salts) and an enzyme can be cross-linked withmethylenebisacrylamide.

[0022] Examples of suitable forms for administration (preferably oraladministration) include pills, tablets, capsules, and powders (e.g., forsprinkling on food or incorporating into a drink). The pill, tablet,capsule, or powder can be coated with a substance capable of protectingthe composition from disintegration in the esophagus but will allowdisintegration as the composition in the stomach and mixing with food topass into the patient's small intestine. The polymer can be administeredalone or in combination with a pharmaceutically acceptable carriersubstance, e.g., magnesium carbonate, lactose, or a phospholipid withwhich the polymer can form a micelle.

[0023] The polymers of the invention can be used to treat patients,preferably humans, with high urinary or serum oxalate levels orhyperoxaluria or who are at risk of high urinary or serum oxalate levelsor hyperoxaluria. For example, patients who can be treated by theadministration of the polymers described herein include those who haveor have had urinary calculi or kidney stones, those who have renaldeficiency due to elevated oxalate levels, those who are on dietscontaining large amounts of oxalate, those who have ileal disease, ilealresection or jejeunoileal bypass, those who have biliary or pancreaticdisease and those with a family history of calculi. Additionally,patients with cardiomyopathy, cardiac conductance disorders, cysticfibrosis, Crohn's disease, renal failure, vulvodynia and depletedcolonies of intestinal Oxalobacter formigenes.

EXAMPLES

[0024] A. Polymer Preparation

[0025] 1. Poly(vinylamine)

[0026] The first step involved the preparation ofethylidenebisacetamide. Acetamide (118 g), acetaldehyde (44.06 g),copper acetate (0.2 g), and water (300 mL) were placed in a 1 L threeneck flask fitted with condenser, thermometer, and mechanical stirred.Concentrated HCl (34 mL) was added and the mixture was heated to 45-50°C. with stirring for 24 hours. The water was then removed in vacuo toleave a thick sludge which formed crystals on cooling to 5° C. Acetone(200 mL) was added and stirred for a few minutes, after which the solidwas filtered off and discarded. The acetone was cooled to 0° C. andsolid was filtered off. This solid was rinsed in 500 mL acetone and airdried 18 hours to yield 31.5 g of ethylidenebis-acetamide.

[0027] The next step involved the preparation of vinylacetamide fromethylidenebisacetamide. Ethylidenebisacetamide (31.05 g), calciumcarbonate (2 g) and celite 541 (2 g) were placed in a 500 mL three neckflask fitted with a thermometer, a mechanical stirrer, and a distillinghead atop a Vigroux column. The mixture was vacuum distilled at 24 mm Hgby heating the pot to 180-225° C. Only a single fraction was collected(10.8 g) which contained a large portion of acetamide in addition to theproduct (determined by NMR). This solid product was dissolved inisopropanol (30 mL) to form the crude vinylacetamide solution used forpolymerization.

[0028] Crude vinylacetamide solution (15 mL), divinylbenzene (1 g,technical grade, 55% pure, mixed isomers), and AIBN (0.3 g) were mixedand heated to reflux under a nitrogen atmosphere for 90 minutes, forminga solid precipitate. The solution was cooled, isopropanol (50 mL) wasadded, and the solid was collected by centrifugation.

[0029] The solid was rinsed twice in isopropanol, once in water, anddried in a vacuum oven to yield 0.8 g of poly(vinylacetamide), which wasused to prepare poly(vinylamine as follows).

[0030] Poly(vinylacetamide) (0.79 g) was placed in a 100 mL one neckflask containing water (25 mL) and conc. HCl(25 mL). The mixture wasrefluxed for 5 days, after which the solid was filtered off, rinsed oncein water, twice in isopropanol, and dried in a vacuum oven to yield 0.77g of product. Infrared spectroscopy indicated that a significant amountof the amide (1656 cm⁻¹) remained and that not much amine (1606 cm⁻¹)was formed. The product of this reaction (˜0.84 g) was suspended in NaOH(46 g) and water (46 g) and heated to boiling (˜140° C.). Due to foamingthe temperature was reduced and maintained at ˜100° C. for 2 hours.Water (100 mL) was added and the solid collected by filtration. Afterrinsing once in water the solid was suspended in water (500 mL) andadjusted to pH 5 with acetic acid. The solid was again filtered off,rinsed with water, then isopropanol, and dried in a vacuum oven to yield0.51 g of product. Infrared spectroscopy indicated that significantamine had been formed.

[0031] 2. Poly(allylamine) hydrochloride

[0032] To a 2 liter, water-jacketed reaction kettle equipped with (1) acondenser topped with a nitrogen gas inlet, 92) a thermometer, and (3) amechanical stirrer was added concentrated hydrochloric acid (360 mL).The acid was cooled to 5° C. using circulating water in the jacket ofthe reaction kettle (water temperature=0° C.). Allylamine (328.5 mL, 250g) was added dropwise with stirring while maintaining the reactiontemperature at 5-10° C. After addition was complete, the mixture wasremoved, placed in a 3 liter one-neck flask, and 206 g of liquid wasremoved by rotary vacuum evaporation at 60° C. Water (20 mL) was thenadded and the liquid was returned to the reaction kettle.Azobis(amidinopropane) dihydrochloride (0.5 g) was suspended in 11 mL ofwater was then added. The resulting reaction mixture was heated to 50°C. under a nitrogen atmosphere with stirring for 24 hours. Additionalazobis(amidinopropane) dihydrochloride (5 mL) suspended in 11 mL ofwater was then added, after which heating and stirring were continuedfor an additional 44 hours.

[0033] At the end of this period, distilled water (100 mL) was added tothe reaction mixture and the liquid mixture allowed to cool withstirring. The mixture was then removed and placed in a 2 literseparatory funnel, after which it was added dropwise to a stirringsolution of methanol (4 L), causing a solid to form. The solid wasremoved by filtration, re-suspended in methanol (4 L), stirred for 1hour, and collected by filtration. The methanol rinse was then repeatedone more time and the solid dried in a vacuum oven to afford 215.1 g ofpoly(allylamine) hydrochloride as a granular white solid.

[0034] 3. Poly(allylamine) hydrochloride crosslinked withepichlorohydrin

[0035] To a 5 gallon vessel was added poly(allylamine) hydrochlorideprepared as described in Example 2 (1 kg) and water (4 L). The mixturewas stirred to dissolve the hydrochloride and the pH was adjusted byadding solid NaOH (284 g). The resulting solution was cooled to roomtemperature, after which epichlorohydrin crosslinking agent (50 mL) wasadded all at once with stirring. The resulting mixture was stirredgently until it gelled (about 35 minutes). The crosslinking reaction wasallowed to proceed for an additional 18 hours at room temperature, afterwhich the polymer gel was removed and placed in portions in a blenderwith a total of 10 L of water. Each portion was blended gently for about3 minutes to form coarse particles which were then stirred for 1 hourand collected by filtration. The solid was rinsed three times bysuspending it in water (10 L, 15 L, 20 L), stirring each suspension for1 hour, and collecting the solid each time by filtration. The resultingsolid was then rinsed once by suspending it in isopropanol (17 L),stirring the mixture for 1 hour, and then collecting the solid byfiltration, after which the solid was dried in a vacuum oven at 50° C.for 18 hours to yield about 677 g of the cross-linked polymer as agranular, brittle, white solid.

[0036] 4. Poly(allylamine) hydrochloride crosslinked withbutanedioldiglycidyl ether

[0037] To a 5 gallon plastic bucket was added poly(allylamine)hydrochloride prepared as described in Example 2 (500 g) and water (2L). The mixture was stirred to dissolve the hydrochloride and the pH wasadjusted to 10 by adding solid NaOH (134.6 g). The resulting solutionwas cooled to room temperature in the bucket, after which1,4-butanedioldiglycidyl ether crosslinking agent (65 mL) was added allat once with stirring. The resulting mixture was stirred gently until itgelled (about 6 minutes). The crosslinking reaction was allowed toproceed for an additional 18 hours at room temperature, after which thepolymer gel was removed and dried in a vacuum oven at 75° C. for 24hours. The dry solid was then ground and sieved to −30 mesh, after whichit was suspended in 6 gallons of water and stirred for 1 hour. The solidwas then filtered off and the rinse process repeated two more times. Theresulting solid was then air dried for 48 hours, followed by drying in avacuum oven at 50° C. for 24 hours to yield about 415 g of thecrosslinked polymer as a white solid.

[0038] 5. Poly(allylamine) hydrochloride crosslinked withethanedioldiglycidyl ether

[0039] To a 100 mL beaker was added poly(allylamine) hydrochlorideprepared as described in Example 2 (10 g) and water (40 mL). The mixturewas stirred to dissolve the hydrochloride and the pH was adjusted to 10by adding solid NaOH. The resulting solution was cooled to roomtemperature in the beaker, after which 1,2-ethanedioldiglycidyl ethercrosslinking agent (2.0 mL) was added all at once with stirring. Theresulting mixture was stirred gently until it gelled (about 4 minutes).The crosslinking reaction was allowed to proceed for an additional 18hours at room temperature, after which the polymer gel was removed andblended in 500 mL of methanol. The solid was then filtered off andsuspended in water (500 mL). After stirring for 1 hour, the solid wasfiltered off and the rinse process repeated. The resulting solid wasrinsed twice in isopropanol (400 mL) and then dried in a vacuum oven at50° C. for 24 hours to yield 8.7 g of the crosslinked polymer as a whitesolid.

[0040] 6. Poly(allylamine) hydrochloride crosslinked withdimethylsuccinate

[0041] To a 500 mL round bottom flask was added poly(allylamine)hydrochloride prepared as described in Example 2 (10 g), methanol (100mL), and triethylamine (10 mL). The mixture was stirred anddimethylsuccinate crosslinking agent (1 mL) was added. The solution washeated to reflux and the stirring discontinued after 30 minutes. After18 hours, the solution was cooled to room temperature, and the solidfiltered off and blended in 400 mL of isopropanol. The solid was thenfiltered off and suspended in water (1 L). After stirring for 1 hour,the solid was filtered off and the rinse process repeated two moretimes. The solid was then rinsed once in isopropanol (800 mL) and driedin a vacuum oven at 50° C. for 24 hours to yield 5.9 g of thecrosslinked polymer as a white solid.

[0042] 7. Poly(allyltrimethylammonium chloride)

[0043] To a 500 mL three necked flask equipped with a magnetic stirrer,a thermometer, and a condenser topped with a nitrogen inlet, was addedpoly(allylamine) crosslinked with epichlorohydrin (5.0 g), methanol (300mL), methyl iodide (20 mL), and sodium carbonate (50 g). The mixture wasthen cooled and water was added to total volume of 2 L. Concentratedhydrochloric acid was added until no further bubbling resulted and theremaining solid was filtered off. The solid was rinsed twice in 10%aqueous NaCl (1 L) by stirring for 1 hour followed by filtration torecover the solid. The solid was then rinsed three times by suspendingit in water (2 L), stirring for 1 hour, and filtering to recover thesolid. Finally, the solid was rinsed as above in methanol and dried in avacuum over at 50° C. for 18 hours to yield 7.7 g of white granularsolid.

[0044] 8. Poly(ethyleneimine)/acryloyl chloride

[0045] Into a 5 L three neck flask equipped with a mechanical stirrer, athermometer, and an additional funnel was added polyethyleneimine (510 gof a 50% aqueous solution (equivalent to 255 g of dry polymer) andisopropanol (2.5 L). Acryloyl chloride (50 g) was added dropwise throughthe addition funnel over a 35 minute period, keeping the temperaturebelow 29° C. The solution was then heated to 60° C. with stirring for 18hours. The solution was cooled and solid immediately filtered off.

[0046] The solid was rinsed three times by suspending it in water (2gallons), stirring for 1 hour, and filtering to recover the solid. Thesolid was rinsed once by suspending it in methanol (2 gallons), stirringfor 30 minutes, and filtering to recover the solid. Finally, the solidwas rinsed as above in isopropanol and dried in a vacuum over at 50° C.for 18 hours to yield 206 g of light orange granular solid.

[0047] 9. Poly(dimethylaminopropylacrylamide)

[0048] Dimethylamino-propylacrylamide (10 g) and methylene-bisacrylamide(1.1 g) were dissolved in 50 mL of water in a 100 mL three neck flask.The solution was stirred under nitrogen for 10 minutes. Potassiumpersulfate (0.3 g) and sodium metabisulfite (0.3 g) were each dissolvedin 2-3 mL of water and then mixed. After a few seconds this solution wasadded to the monomer solution, still under nitrogen. A gel formedimmediately and was allowed to sit overnight. The gel was removed andblended with 500 mL of isopropanol. The solid was filtered off andrinsed three times with acetone. The solid white powder was filtered offand dried in a vacuum oven to yield 6.1 g.

[0049] 10. Poly(Methacrylamidopropyltrimethylammoniumchloride)=[Poly(MAPTAC)]

[0050] [3-(Methacryloylamino)propyl]trimethylammonium chloride (38 mL of50% aqueous solution) and methylenebis-methacrylamide (2.2 g) werestirred in a beaker at room temperature. Methanol (10 mL was added andthe solution was warmed to 40° C. to fully dissolve the bisacrylamide.Potassium persulfate (0.4 g) was added and the solution stirred for 2minutes. Potassium metabisulfite (0.4 g) was added and stirring wascontinued. After 5 minutes the solution was put under a nitrogenatmosphere. After 20 minutes the solution contained significantprecipitate and the solution was allowed to sit overnight. The solid waswashed three times with isopropanol and collected by filtration. Thesolid was then suspended in water 500 (mL) and stirred for several hoursbefore being collected by centrifugation. The solid was again washedwith water and collected by filtration. The solid was then dried in avacuum oven to yield 21.96 g.

[0051] 11. Poly(ethyleneimine) “A”

[0052] Polyethyleneimine (50 g of a 50% aqueous solution; ScientificPolymer Products) was dissolved in water (100 mL). Epichlorohydrin (4.6mL) was added dropwise. The solution was heated to 55° C. for 4 hours,after which it had gelled. The gel was removed, blended with water (1 L)and the solid was filtered off. It was resuspended in water (2 L) andstirred for 10 minutes. The solid was filtered off, the rinse repeatedonce with water and twice with isopropanol, and the resulting gel wasdried in a vacuum oven to yield 26.3 g of a rubbery solid.Poly(ethyleneimine) “B” and Poly(ethyleneimine) “C” were made in asimilar manner, except using 9.2 and 2.3 mL of epichlorohydrin,respectively.

[0053] 12. Poly(methylmethacrylate-co-divinylbenzene)

[0054] Methylmethacrylate (50 g) and divinylbenzene (5 g) andazobisiso-butyronitrile (1.0 g) were dissolved in isopropanol (500 mL)and heated to reflux for 18 hours under a nitrogen 14 atmosphere. Thesolid white precipitate was filtered off, rinsed once in acetone(collected by centrifugation), once in water (collected by filtration)and dried in a vacuum oven to yield 19.4 g.

[0055] 13. Poly(diethylenetriaminemethacrylamide)

[0056] Poly(methyl-methacrylate-co-divinylbenzene) (20 g) was suspendedin diethylenetriamine (200 mL) and heated to reflux under a nitrogenatmosphere for 18 hours. The solid was collected by filtration,resuspended in water (500 mL), stirred 30 minutes, filtered off,resuspended in water (500 mL), stirred 30 minutes, filtered off, rinsedbriefly in isopropanol, and dried in a vacuum oven to yield 18.0 g.

[0057] Polypentaethylenehexaminemethacrylamide),Poly(tetraethylenepentaminemethacrylamide), andPoly(trie-thylenetetraaminemethacrylamide) were made in a manner similarto poly(diethylenetriaminemethacrylamide) from pentaethylenehexamine,tetraethylenepentamine, and triethylenetetraamine, respectively.

[0058] 14. Poly(methylmethacrylate/PEI)

[0059] Poly(methylmethacrylate-co-divinylbenzene) (1.0 g) was added to amixture containing hexanol (9150 mL) and polyethyleneimine (15 g in 15 gwater). The mixture was heated to reflux under nitrogen for 4 days. Thereaction was cooled and the solid was filtered off, suspended inmethanol (300 mL), stirred 1 hour, and filtered off. The rinse wasrepeated once with isopropanol and the solid was dried in a vacuum ovento yield 0.71 g.

[0060] 15. Poly(aminoethylmethacrylamide)Poly(methylmethacrylate-co-divinylbenzene) (20 g) was suspended inethylenediamine 9200 mL) and heated to reflux under a nitrogenatmosphere for 3 days. The solid was collected by centrifugation, washedby resuspending it in water (500 mL), stirring for 30 minutes, andfiltering off the solid. The solid was washed twice more in water, oncein isopropanol, and dried in a vacuum oven to yield 17.3 g.

[0061] 16. Poly(diethylaminopropylmethacrylamide)

[0062] Poly(methyl-methacrylate-co-divinylbenzene) (20 g) was suspendedin diethylaminopropylamine (200 mL) and heated to reflux under anitrogen atmosphere for 18 hours. The solid was collected by filtration,resuspended in water (500 mL), filtered off, resuspended in water (500mL), collected by filtration, rinsed briefly in isopropanol, and driedin a vacuum oven to yield 8.2 g.

[0063] 17. NHS-acrylate

[0064] N-Hydroxysuccinimide (NHS, 157.5 g) was dissolved in chloroform(2300 mL) in a 5 L flask. The solution was cooled to 0° C. and acryloylchloride (132 g) was added dropwise, keeping the temperature 2° C. Afteraddition was complete, the solution was stirred for 1.5 hours, rinsedwith water (1100 mL) in a separatory funnel and dried over anhydroussodium sulfate. The solvent was removed under vacuum and a small amountof ethyl acetate was added to the residue. This mixture was poured intohexane (200 mL) with stirring. The solution was heated to reflux, addingmore ethyl acetate (400 mL). The insoluble NHS was filtered off, hexane(1 L) was added, the solution was heated to reflux, ethyl acetate (400mL) was added, and the solution allowed to cool to <10° C. The solid wasthen filtered off and dried in a vacuum oven to yield 125.9 g. A secondcrop of 80 g was subsequently collected by further cooling.

[0065] 18. Poly(NHS-acrylate)

[0066] NHS-acrylate (28.5 g), methylenebis-acrylamide (1.5 g) andtetrahydrofuran (500 mL) were mixed in a 1 L flask and heated to 50° C.under a nitrogen atmosphere. Azobisisobutyronitrile (0.2 g) was added,the solution was stirred for 1 hour, filtered to remove excessN-hydroxysuccinimide, and heated to 50° C. for 4.5 hours under anitrogen atmosphere. The solution was then cooled and the solid wasfiltered off, rinsed in tetrahydrofuran, and dried in a vacuum oven toyield 16.1 g.

[0067] 19. Poly(guanidinobutylacrylamide)

[0068] Poly(NHS-acrylate) (1.5 g) was suspended in water (25 mL)containing agmatine (1.5 g) which had been adjusted to pH 9 with solidNaOH. The solution was stirred for 4 days, after which time the pH haddropped to 6.3. Water was added to a total of 500 mL, the solution wasstirred for 30 minutes and the solid was filtered off. The solid wasrinsed twice in water, twice in isopropanol, and dried in a vacuum ovento yield 0.45 g.

[0069] 20. Poly(methacryloyl chloride)

[0070] Methacryloyl chloride (20 mL), divinyl benzene (4 mL of 80%purity), AIBN (0.4 g), and THF (150 mL) were stirred at 60° C. under anitrogen atmosphere for 18 hours. The solution was cooled and the solidwas filtered off, rinsed in THF, then acetone, and dried in a vacuumoven to yield 8.1 g.

[0071] 21. Poly(guanidinobutylmethacrylamide)

[0072] Poly(methacryloyl chloride) (0.5 g), agmatine sulfate (1.0 g),triethylamine (2.5 mL), and acetone (50 mL) were stirred together for 4days. Water (100 niL) was added and the mixture stirred for 6 hours. Thesolid was filtered off and washed by resuspending in water (500 mL),stirring for 30 minutes, and filtering off the solid. The wash wasrepeated twice in water, once in methanol, and the solid was dried in avacuum oven to yield 0.41 g.

[0073] 22. Poly(guanidinoacrylamide)

[0074] The procedure for poly-(guanidinobutylacrylamide) was followedsubstituting aminoguanidine bicarbonate (5.0 g) for the agmatine,yielding 0.75 g.

[0075] 23. Poly(PEH/EPI)

[0076] Epichlorohydrin (1.5 g) was added dropwise to a solutioncontaining pentaethylenehexamine (PEH) (20 g) and water (100 mL),keeping the temperature between 65° C. The solution was stirred until itgelled and heating was continued for 4 hours (at 65° C.). After sittingovernight at room temperature the gel was removed and blended with water(1 L). The solid was filtered off, water was added (1 L), and theblending and filtration were repeated. The gel was suspended inisopropanol and the resulting solid was collected by filtration anddried in a vacuum oven to yield 28.2 g.

[0077] 24. Ethylidenebisacetamide

[0078] Acetamide (118 g), acetaldehyde (44.06 g), copper acetate (0.2g), and water (300 mL) were placed in a 1 L three neck flask fitted withcondenser, thermometer, and mechanical stirred. Concentrated HCl (34 mL)was added and the mixture was heated to 45-50° C. with stirring for 24hours. The water was then removed in vacuo to leave a thick sludge whichformed crystals on cooling to 5° C. Acetone (200 mL) was added andstirred for a few minutes after which the solid was filtered off anddiscarded. The acetone was cooled to 0° C. and solid was filtered off.This solid was rinsed in 500 mL acetone and air dried 18 hours to yield31.5 g.

[0079] 25. Vinylacetamide

[0080] Ethylidenebisacetamide (31.05), calcium carbonate (2 g) andcelite 541 (2 g) were placed in a 500 mL three neck flask fitted with athermometer, a mechanical stirrer, and a distilling head atop a vigrouxcolumn. The mixture was vacuum distilled at 35 mm Hg by heating the potto 180-225° C. Only a single fraction was collected (10.8 g) whichcontained a large portion of acetamide in addition to the product(determined by NMR). This solid product was dissolved in isopropanol (30mL) to form the crude solution used for polymerization.

[0081] 26. Poly(vinylacetamide)

[0082] Crude vinylacetamide solution (15 mL), divinylbenzene (1 g,technical grade, 55% pure, mixed isomers), and AIBN (0.3 g) were mixedand heated to reflux under a nitrogen atmosphere for 90 minutes, forminga solid precipitate. The solution was cooled, isopropanol (50 mL) wasadded, and the solid was collected by centrifugation. The solid wasrinsed twice in isopropanol, once in water, and dried in a vacuum ovento yield 0.8 g.

[0083] 27. Poly(vinylamine)

[0084] Poly(vinylacetamide) (0.79 g) was placed in a 100 mL one neckflask containing water 25 mL and concentrated HCl 25 mL. The mixture wasrefluxed for 5 days, the solid was filtered off, rinsed once in water,twice in isopropanol, and dried in a vacuum oven to yield 0.77 g. Theproduct of this reaction (˜0.84 g) was suspended in NaOH (46 g) andwater (46 g) and heated to boiling (˜140° C.). Due to foaming thetemperature was reduced and maintained at ˜100° C. for 2 hours. Water(100 mL) was added and the solid collected by filtration. After rinsingonce in water the solid was suspended in water (500 mL) and adjusted topH 5 with acetic acid. The solid was again filtered off, rinsed withwater, then the isopropanol, and dried in a vacuum oven to yield 0.51 g.

[0085] 28. Poly(ethyleneimine) Salts

[0086] Polyethyleneimine (25 g dissolved in 25 g water) was dissolved inwater (100 20 mL) and mixed with toluene (1 L). Epichlorohydrin (2.3 mL)was added and the mixture heated to 60° C. with vigorous mechanicalstirring for 18 hours. The mixture was cooled and the solid filteredoff, resuspended in methanol (2 L), stirred 1 hour, and collected bycentrifugation. The solid was suspended in water (2 L), stirred 1 hour,filtered off, suspended in water (4 L), stirred 1 hour, and againfiltered off. The solid was suspended in acetone (4 L) and stirred 15minutes, the liquid was poured off, acetone (2 L) was added, the mixturewas stirred 15 minutes, the acetone was again poured off, and the solidwas dried in a vacuum oven to form intermediate “D”.

[0087] 29. Poly(ethyleneimine sulfate A)

[0088] Intermediate “D” (1.0 g) was suspended in water (150 mL), stirred30 minutes, and partially neutralized with sulfuric acid (1.1 g). Themixture was stirred an additional 30 minutes, the solid was filteredoff, resuspended in methanol (200 mL), stirred 5 minutes, filtered off,and dried in a vacuum oven. 30. Poly(ethyleneimine sulfate B)Intermediate “D” (1.0 g) was suspended in water (150 mL), stirred 30minutes, and partially neutralized with sulfuric acid (0.57 g). Themixture was stirred an additional 30 minutes, the solid was filteredoff, resuspended in methanol (200 mL), stirred 5 minutes, filtered off,and dried in a vacuum oven.

[0089] 31. Poly(ethyleneimine sulfate C)

[0090] Intermediate “D” (1.0 g) was suspended in water (150 mL), stirred30 minutes, and partially neutralized with sulfuric acid (0.28 g). Themixture was stirred an additional 30 minutes, the solid was filteredoff, resuspended in methanol (200 mL), stirred 5 minutes, filtered off,and dried in a vacuum oven.

[0091] 32. Poly(ethyleneimine sulfate D)

[0092] Intermediate “D” (1.0 g) was suspended in water (150 mL), stirred30 minutes, and partially neutralized with sulfuric acid (0.11 g). Themixture was stirred an additional 30 minutes, the solid was filteredoff, resuspended in methanol (200 mL), stirred 5 minutes, filtered off,and dried in a vacuum oven.

[0093] 33. Poly(ethyleneimine tartrate A)

[0094] Intermediate “D” (1.0 g) was suspended in water (150 mL), stirred30 minutes, and partially neutralized with tartaric acid (1.72 g). Themixture was stirred an additional 30 minutes, the solid was filteredoff, resuspended in methanol (200 mL), stirred 5 minutes, filtered off,and dried in a vacuum oven.

[0095] 34. Poly(ethyleneimine tartrate B)

[0096] Intermediate “D” (1.0 g) was suspended in water (150 mL), stirred30 minutes, and partially neutralized with tartaric acid (0.86 g). Themixture was stirred an additional 30 minutes, the solid was filteredoff, resuspended in methanol (200 mL), stirred 5 minutes, filtered off,and dried in a vacuum oven.

[0097] 35. Poly(ethyleneimine tartrate C)

[0098] Intermediate “D” (1.0 g) was suspended in water (150 mL), stirred30 minutes, and partially neutralized with tartaric acid (0.43 g). Themixture was stirred an additional 30 minutes, the solid was filteredoff, resuspended in methanol (200 mL), stirred 5 minutes, filtered off,and dried in a vacuum oven.

[0099] 36. Poly(ethyleneimine ascorbate A)

[0100] Intermediate “D” (1.0 g) was suspended in water (150 mL), stirred30 minutes, and partially neutralized with ascorbic acid (4.05 g). Themixture was stirred an additional 30 minutes, the solid was filteredoff, resuspended in methanol (200 mL), stirred 5 minutes, filtered off,and dried in a vacuum oven.

[0101] 37. Poly(ethyleneimine ascorbate B)

[0102] Intermediate “D” (1.0 g) was suspended in water (150 mL), stirred30 minutes, and partially neutralized with ascorbic acid (2.02 g). Themixture was stirred an additional 30 minutes, the solid was filteredoff, resuspended in methanol (200 mL), stirred 5 minutes, filtered off,and dried in a vacuum oven.

[0103] 38. Poly(ethyleneimine ascorbate C)

[0104] Intermediate “D” (1.0 g) was suspended in water (150 mL), stirred30 minutes, and partially neutralized with ascorbic acid (1.01 g). Themixture was stirred an additional 30 minutes, the solid was filteredoff, resuspended in methanol (200 mL), stirred 5 minutes, filtered off,and dried in a vacuum oven.

[0105] 39. Poly(ethyleneimine citrate A)

[0106] Intermediate “D” (1.0 g) was suspended in water (150 mL), stirred30 minutes, and partially neutralized with citric acid (1.47 g). Themixture was stirred an additional 30 minutes, the solid was filteredoff, resuspended in methanol (200 mL), stirred 5 minutes, filtered off,and dried in a vacuum oven.

[0107] 40. Poly(ethyleneimine citrate B)

[0108] Intermediate “D” (1.0 g) was suspended in water (150 mL), stirred30 minutes, and partially neutralized with citric acid (0.74 g). Themixture was stirred an additional 30 minutes, the solid was filteredoff, resuspended in methanol (200 mL), stirred 5 minutes, filtered off,and dried in a vacuum oven.

[0109] 41. Poly(ethyleneimine citrate C)

[0110] Intermediate “D” (1.0 g) was suspended in water (150 mL), stirred30 minutes, and partially neutralized with citric acid (0.37 g). Themixture was stirred an additional 30 minutes, the solid was filteredoff, resuspended in methanol (200 mL), stirred 5 minutes, filtered off,and dried in a vacuum oven.

[0111] 42. Poly(ethyleneimine succinate A)

[0112] Intermediate “D” (1.0 g) was suspended in water (150 mL), stirred30 minutes, and partially neutralized with succinic acid (1.36 g). Themixture was stirred an additional 30 minutes, the solid was filteredoff, resuspended in methanol (200 mL), stirred 5 minutes, filtered off,and dried in a vacuum oven.

[0113] 43. Poly(ethyleneimine succinate B)

[0114] Intermediate “D” (1.0 g) was suspended in water (150 mL), stirred30 minutes, and partially neutralized with succinic acid (0.68 g). Themixture was stirred an additional 30 minutes, the solid was filteredoff, resuspended in methanol (200 mL), stirred 5 minutes, filtered off,and dried in a vacuum oven.

[0115] 44. Poly(ethyleneimine chloride)

[0116] Polyethyleneimine (100 g in 100 g water) was dissolved in water(640 mL additional) and the pH was adjusted to 10 with concentrated HCl.Isopropanol (1.6 L) was added, followed by epichlorohydrin (19.2 mL).The mixture was stirred under nitrogen for 18 hours at 60° C. The solidswere filtered off and rinsed with methanol (300 mL) on the funnel. Thesolid was rinsed by resuspending it in methanol (4 L), stirring 30minutes, and filtering off the solid. The rinse was repeated twice withmethanol, followed by resuspension in water (1 gallon). The pH wasadjusted to 1.0 with concentrated HCl, the solid was filtered off,resuspended in water (1 gallon), the pH again adjusted to 1.0 withconcentrated HCl, the mixture stirred 30 minutes, and the solid filteredoff. The methanol rinse was again repeated and the solid dried in avacuum oven to yield 112.4 g.

[0117] 45. Poly(dimethylethyleneimine chloride)

[0118] Poly(ethyleneimine chloride) (5.0 g) was suspended in methanol(300 mL) and sodium carbonate (50 g) was added. Methyl iodide (20 mL)was added and the mixture heated to reflux for 3 days. Water was addedto reach a total volume of 500 mL, the mixture stirred for 15 minutes,and the solid filtered off. The solid was suspended in water (500 mL),stirred 30 minutes, and filtered. The solid was suspended in water (1L), the pH adjusted to 7.0 with concentrated HCl, and the mixturestirred for 10 minutes. The solid was filtered off, resuspended inisopropanol (1 L), stirred 30 minutes, filtered off, and dried in avacuum oven to yield 6.33 g.

[0119] 46. Poly(methacryloyl chloride)

[0120] Methacryloyl chloride (20 mL), divinyl benzene (4 mL of 80%purity), AIBN (0.4 g), and THF (150 mL) were stirred at 60° C. under anitrogen atmosphere for 18 hours. The solution was cooled, and the solidwas filtered off, rinsed in THF, then acetone, and dried in a vacuumoven to yield 8.1 g.

[0121] 47. Poly(guanidinobutylmethacrylamide)

[0122] Poly(methacryloyl chloride) (0.5 g), agmatine sulfate (1.0 g),triethylamine (2.5 mL), and acetone (50 mL) were stirred together for 4days. Water (100 mL) was added, and the mixture stirred for 6 hours. Thesolid was filtered off, washed by resuspending in water (500 mL),stirring for 30 minutes, and filtering off the solid. The wash wasrepeated twice in water, once in methanol, and the solid was dried in avacuum oven to yield 0.41 g.

[0123] 48. Poly(PEH/EPI)

[0124] Epichlorohydrin (21.5 g) was added dropwise to a solutioncontaining pentaethylenehexamine (20 g) and water (100 mL), keeping thetemperature below 65° C. The solution was stirred until it gelled, andheating was continued for 4 hours (at 65° C.). After sitting overnightat room temperature, the gel was removed and blended with water (1 L).The solid was filtered off, water was added (1 L), and the blending andfiltration were repeated. The gel was suspended in isopropanol, and theresulting solid was collected by filtration and dried in a vacuum ovento yield 28.2 g.

[0125] 49. Poly(TAEA-acrylamide)

[0126] Poly(NHS-acrylate) (4.4 g) was suspended in a solution containingwater (100 mL) and tris(2-aminoethyl)amine (30 mL) which had beenadjusted to pH 9 with concentrated HCl. After 4 days of stirring, thesolid was filtered off, and the wash repeated. The solid was then rinsedbriefly with water twice, isopropanol once, and dried in a vacuum ovento yield 3.4 g.

[0127] 50. Poly(PEH-acrylamide)

[0128] Poly(NHS-acrylate) (5.0 g) was suspended in a solution containingwater (100 mL) and pentaethylene hexamine (30 mL) which had beenadjusted to pH 10 with concentrated HCl. After 4 days of stirring, thesolid was filtered off and resuspended in water (500 mL). The mixturewas stirred for 4 hours, the solid was filtered off, and the washrepeated. The solid was then rinsed briefly with water twice,isopropanol once, and dried in a vacuum oven to yield 4.7 g.

[0129] 51. Poly(MI/EPI)

[0130] To a 500 mL flask was added 2-methylimidazole (41.00 g, 0.50 mol)and water (100 mL). The solution was heated to 55° C., andepichlorohydrin (46.3 g. 0.50 mol) was added dropwise over 100 minutes.The maximum temperature reached during the addition was 75° C. When theaddition was complete, the solution was heated to −90° C. and held atthat temperature for 18 hours. In the morning, the reaction was cooledto 45° C., and epichlorohydrin (8.7 g, 0.094 mol) was added dropwise.After the addition was complete, the solution was stirred at 45° C. for2 hours. At this point, a solution of sodium hydroxide (3.78 g, 0.094mol) in water (15 mL) was prepared. The reaction was cooled, and thesodium hydroxide solution was added dropwise at 28° C. over 10 minutes.The solution was stirred for an additional 15 minutes and thentransferred to a beaker and heated to 95° C. on a hot plate. When thereaction solidified, it was placed in an oven at 125° C. for 5 hours tocure. After cooling to room temperature, the polymer was broken up andadded to 2000 mL of water. The mixture was allowed to stand for 3 hoursand then blended in two portions. The hydrated gel was filtered and thendehydrated with isopropanol in two steps in the blender. Filtration andvacuum drying afforded 83.51 g of title polymer.

[0131] 52. Poly(2-acrylamido-2-methyl propane sulfonic acid) (10%crosslinking) containing Oxalate Decarboxylase

[0132] To a 10 mL beaker was added 2-acrylamido-2-methylpropane sulfonicacid (0.25 g) water (2.5 mL), methylenebisacrylamide (0.028 g), andoxalate decarboxylase (3 mg;

[0133] from C. Velutipes; Sigma). Nitrogen gas was bubbled through thesample for 10 minutes, followed by the addition of potassium persulfate(3 mg) and potassium metabisulfite (3 mg). The mixture was allowed tosit for 18 hours and was broken up in a blender in aqueous sodiumcitrate (500 mL; 0.2 M). The solid was collected by filtration andtested as is.

[0134] 53. Poly(2-acrylamido-2-methyl propane sulfonic acid) (5%crosslinking) containing Oxalate Decarboxylase

[0135] To a 10 mL beaker was added 2-acrylamido-2-methylpropane sulfoneacid (0.25 g) water (2.5 mL), methylenebisacrylamide (0.014 g), andoxalate decarboxylase (3 mg;

[0136] from C. Velutipes; Sigma). Nitrogen gas was bubbled through thesample for 10 minutes, followed by the addition of potassium persulfate(3 mg) and potassium metabisulfite (3 mg). The mixture was allowed tosit for 18 hours, followed by a second addition of potassium persulfate(3 mg) and potassium metabisulfite (3 mg). After an additional 18 hours,the gel was broken up in a blender in aqueous sodium citrate (500 mL;0.2 M; pH 4). The solid was collected by filtration and tested as is.

[0137] 54. Copoly(Acrylamide-co-2-acrylamido-2-methyl propane sulfonicacid) (10% crosslinking) containing Oxalate Decarboxylase

[0138] To a 10 mL beaker was added 2-acrylamido-2-methylpropane sulfonicacid (0.186 g), acrylamide (0.064 g), water 2.5 mL),methylenebisacrylamide (0.028 g), and oxalate decarboxylase (3 mg; fromC. Velutipes; Sigma). Nitrogen gas was bubbled through the sample for 10minutes, followed by the addition of potassium persulfate (6 mg) andpotassium metabisulfite (6 mg). The mixture was allowed to sit for 18hours and was broken up in a blender in aqueous sodium citrate (500 mL;0.2 M; pH 4). The solid was collected by filtration and tested as is.

[0139] 55. Poly(Acrylamide) containing Oxalate Decarboxylase

[0140] To a 10 mL beaker was added acrylamide (0.25 g), water (2.5 mL),methylenebisacrylamide (0.027 g), and oxalate decarboxylase (3 mg; fromC. Velutipes; Sigma). Nitrogen gas was bubbled through the sample for 10minutes, followed by the addition of potassium persulfate (6 mg) andpotassium metabisulfite (6 mg). The mixture was allowed to sit for 18hours and was broken up in a blender in aqueous sodium citrate (500 mL;0.2 M; pH 4). The solid was collected by filtration and tested as is.

[0141] 56. Polyallylamine crosslinked with epichlorohydrin

[0142] An aqueous solution of poly(allylamine hydrochloride) (500 lb ofa 50.7% aqueous solution) was diluted with water (751 lb) andneutralized with aqueous sodium hydroxide (171 lb of a 50% aqueoussolution). The solution was cooled to approximately 25° C., andacetonitrile (1340 lb) and epichlorohydrin (26.2 lb) were added. Thesolution was stirred vigorously for 21 hours. During this time, thereactor contents changed from two liquid phases to a slurry of particlesin a liquid. The solid gel product was isolated by filtration. The gelwas washed in an elutriation process with water (136,708 lb). The gelwas isolated by filtration and rinsed with isopropanol. The gel wasslurried with isopropanol (1269 lb) and isolated by filtration. Theisopropanol/water wet gel was dried in a vacuum dryer at 60° C. Thedried product was ground to pass through a 50 mesh screen to give aproduct suitable for pharmacologic use (166 lb, 73%).

[0143] In Vitro Testing

[0144] Some embodiments were tested by stirring them in anoxalate-containing solution at pH 7, typically for 3 hours. The solutionwas designed to mimic the conditions present in the small intestine.Most tests were run using 1 mM oxalate solution, but some tests usedhigher concentrations. The table below shows the exact test solution.

[0145] Solution Contents

[0146] 1 mM Oxalic Acid

[0147] 80 mM Sodium Chloride

[0148] 30 mM Sodium Carbonate

[0149] Adjusted to pH 7 with concentrated HCl

[0150] The pH was adjusted to pH 7, once at the start of the test andagain at the end of the test, using either 1 M NaOH or 1 M HCl. After 3hours (unless otherwise indicated), the polymer was filtered, and theresidual oxalate concentration in the test solution was determinedspectrophotometrically. The difference between the initial oxalateconcentration and the final concentration was used to determine theamount of oxalate bound to, or destroyed by, the polymer. This result isexpressed in milliequivalents per gram of starting polymer (meq/g).

[0151] The table below shows the results obtained for several examples.Higher numbers indicate a more effective polymer. Polymer Oxalate Bound(meq/g)* Polyethyleneimine “A” 0.24 Polyethyleneimine “B” 0.09Poly(MI/EPI) 0.08 Poly(dimethylaminopropylacrylamide) 0.08 Poly(PEH/EP)0.07 Poly(diethylenetriaminemethacrylamide) 0.04 Poly(MAPTAC) 0.04Poly(PEH-acrylamide) 0.02 Poly(aminopropylacrylamide) HCl 0.01Poly(TAEA-acrylamide) 0.01 Poly(guanidinobutylmethacrylamide) 0.01

[0152] For comparison purposes, the table below shows results obtainedin similar tests using other oxalate-binding materials. By comparison tothe known oxalate binders shown below, the polymers of the presentinvention are potent oxalate binding agents. Polymer Oxalate Bound(meq/g)* Calcium Lactate 1.8 Ox-Absorb ® 0.09 Aluminum Hydroxide, DriedGel 0.04

[0153] Oxalate binding was also tested at concentrations other thanthose in the previous examples. The polymers of the present inventionbind more oxalate as the oxalate concentration rises.

[0154] Polymers of the present invention that contain oxalate degradingenzymes (e.g., oxalate decarboxylase) can also be tested in a similarmanner. The table below shows the effectiveness of several of thesematerials. From the amount of oxalate destroyed per gram of dryequivalent polymer, these materials are potent oxalate eliminatingagents. Oxalate Destroyed Polymer Enzyme pH (meq/g)* Acrylamide OxalateDecarboxylase 3 1.5 10% x-link Oxalate Decarboxylase 5 0.3 OxalateDecarboxylase 7 — AMPS Oxalate Decarboxylase 3 0.6 5% x-link OxalateDecarboxylase 5 0.5 Oxalate Decarboxylase 7 0.5 AMPS OxalateDecarboxylase 3 0.6 10% x-link Oxalate Decarboxylase 5 1.0 OxalateDecarboxylase 7 — AMPS/Acrylamide Oxalate Decarboxylase 3 0.40 10%x-link Oxalate Decarboxylase 5 .3 Oxalate Decarboxylase 7 —

[0155] While this invention has been particularly shown and describedwith references to preferred embodiments thereof, it will be understoodby those skilled in the art that various changes in form and details maybe made therein without departing from the scope of the inventionencompassed by the appended claims.

What is claimed is:
 1. A method for reducing oxalate levels in a patient in need thereof comprising administering to said patient a therapeutically effective amount of one or more aliphatic amine polymers.
 2. The method of claim 1 wherein the polymer is characterized by a repeat unit having a formula selected from the group consisting of:

and salts and copolymers thereof, where n is a positive integer and x is zero or an integer between 1 and about 4, y and z are integers of one or more and R, R₁, R₂ and R₃, independently, is H or a substituted or unsubstituted alkyl, alkylamino or aryl group.
 3. The method of claim 2 wherein said polymer is crosslinked by means of a multifunctional crosslinking agent, said agent being present in an amount from about 0.5-25% by weight, based upon the combined weight of monomer and crosslinking agent.
 4. The method of claim 3 wherein said crosslinking agent is present in an amount from about 2.5-20% by weight, based upon the combined weight of monomer and crosslinking agent.
 5. The method of claim 3 wherein said crosslinking agent comprises epichlorohydrin.
 6. The method of claim 3 wherein the polymer is a homopolymer.
 7. The method of claim 3 wherein the polymer is a polyallylamine.
 8. The method of claim 3 wherein the polymer is a polydiallylamine.
 9. The method of claim 5 wherein the polymer is a polyvinylamine.
 10. The polymer according to claim 3 wherein at least one of R, R₁, R₂, R₃ and R₄ in each formula is hydrogen. 